[Lintaro]

Greetings!

My team and I are going to try and carry out this reaction in our lab:


The theory is that the aniline will act as a nucleophile and substitute the chlorine through the SN2 mechanism, with pyridine as the catalyst. Though as the title of this post implies, we could use some tips on how to make this reaction work since we haven't actually carried it out yet. Therefore, we would appreciate it a lot if you guys could give us some tips on the amount of reactants that we should use, or if we could get better conditions for the reaction to give maximum yield.

Any links to papers/journals about this kind of synthesis are also deeply appreciated. Thank you very much 

[wildfyr]

Do this with 1.1 equivalents dry pyridine in dry DCM or THF. Add the aniline slowly. Let it stir overnight under inert gas. Afterwords, wash it with dilute HCl solution, then sodium bicarbonate solution, then water. It will work absolutely perfectly, and your product will be totally clean, with a yield above 90% if you have things dry enough.

[Lintaro]

Do this with 1.1 equivalents dry pyridine in dry DCM or THF. Add the aniline slowly. Let it stir overnight under inert gas. Afterwords, wash it with dilute HCl solution, then sodium bicarbonate solution, then water. It will work absolutely perfectly, and your product will be totally clean, with a yield above 90% if you have things dry enough.

Thank you very much for your answer! We will definitely give this method a shot.

Additionally, could you give us your reasoning on this methodology? Perhaps a link to a paper or a website? Once again, we can't thank you enough 

[hypervalent_iodine]

I perform a lot of very similar reactions myself. Best way I've found is to add the pyridine (dry) to the amine in freshly distilled THF under argon (or N₂), and then add the acid chloride to this at 0°C drop wise. I think it's more common to do as wildfyr suggested and add the amine to the acid chloride, but I have never had any issue doing it the other way. I should note that cooling the reaction during this addition is very necessary; it heats up quite a lot and releases HCl gas.

You will want to have it under an Ar or N₂ ballon rather than attached to any manifold as well. Once it's added, you can warm to room temperature or reflux. I generally let it go overnight and then quench with 1M HCl under argon.

If you are lucky, acid base work up will do the trick in terms of purification. I guess it depends on your amine. The amines I work with are not quite as nucleophilic, and I have to do a few other things in order to purify. Namely, I wash the residue with cold solvent (depends on the product, but often this works well with EtOAc) and then recrystallise the collected solid in whatever works (EtOAc and PS, usually).

One other thing: quality of your reagents is very important. Everything should be dry. I boosted my yields from ~20% to 80% just by distilling the chloroacetyl chloride I was using prior to the reaction (incidentally, one of the worst things I've ever had to distil).

[hypervalent_iodine]

Do this with 1.1 equivalents dry pyridine in dry DCM or THF. Add the aniline slowly. Let it stir overnight under inert gas. Afterwords, wash it with dilute HCl solution, then sodium bicarbonate solution, then water. It will work absolutely perfectly, and your product will be totally clean, with a yield above 90% if you have things dry enough.

Thank you very much for your answer! We will definitely give this method a shot.

Additionally, could you give us your reasoning on this methodology? Perhaps a link to a paper or a website? Once again, we can't thank you enough 

I found this paper to be quite useful:

http://www.sciencedirect.com/science/article/pii/S0040403909007898

Which reminds me, you could try K₃PO₄ instead of pyridine. I tried this myself and found that purification was much easier, but the yields did suffer a bit.

[phth]

Do this with 1.1 equivalents dry pyridine in dry DCM or THF. Add the aniline slowly. Let it stir overnight under inert gas. Afterwords, wash it with dilute HCl solution, then sodium bicarbonate solution, then water. It will work absolutely perfectly, and your product will be totally clean, with a yield above 90% if you have things dry enough.

Thank you very much for your answer! We will definitely give this method a shot.

Additionally, could you give us your reasoning on this methodology? Perhaps a link to a paper or a website? Once again, we can't thank you enough 

I found this paper to be quite useful:

http://www.sciencedirect.com/science/article/pii/S0040403909007898

Which reminds me, you could try K₃PO₄ instead of pyridine. I tried this myself and found that purification was much easier, but the yields did suffer a bit.

Mortar&pestle, calcine the base  ;p

[hypervalent_iodine]

Do this with 1.1 equivalents dry pyridine in dry DCM or THF. Add the aniline slowly. Let it stir overnight under inert gas. Afterwords, wash it with dilute HCl solution, then sodium bicarbonate solution, then water. It will work absolutely perfectly, and your product will be totally clean, with a yield above 90% if you have things dry enough.

Thank you very much for your answer! We will definitely give this method a shot.

Additionally, could you give us your reasoning on this methodology? Perhaps a link to a paper or a website? Once again, we can't thank you enough 

I found this paper to be quite useful:

http://www.sciencedirect.com/science/article/pii/S0040403909007898

Which reminds me, you could try K₃PO₄ instead of pyridine. I tried this myself and found that purification was much easier, but the yields did suffer a bit.

Mortar&pestle, calcine the base  ;p

Eh? Not sure what you're getting at here? I made the K₃PO₄ myself from dibasic, and I can promise you it was both sufficiently powdered and dried by the time I was done.

[wildfyr]

I said to add the aniline slowly to the acid chloride because it has the alkyl halide as well and I want to avoid dimer. The acid chloride is so much more reactive that its unlikely, but its so simple to avoid. And I don't like K3PO4 because its harder to dry than pyridine (leave over sieves for a day and youre done)

[hypervalent_iodine]

I said to add the aniline slowly to the acid chloride because it has the alkyl halide as well and I want to avoid dimer. The acid chloride is so much more reactive that its unlikely, but its so simple to avoid. And I don't like K3PO4 because its harder to dry than pyridine (leave over sieves for a day and youre done)

Yes, sorry, I should have mentioned that. It isn't a problem for my systems because the anime is not very nucleophilic. Can also confirm that the K₃PO₄ is a pain to dry. IIRC, I had it drying under vacuum with heat overnight. Not terribly difficult, just long.